Single Unit Oral Dose Pharmaceutical Composition Comprising Levodopa, Carbidopa And Entacapone Or Salts Thereof

ABSTRACT

There is provided a single unit oral dose pharmaceutical composition comprising a) levodopa or salts thereof from about 50 mg to about 300 mg in extended release form, b) carbidopa or salts thereof from about 10 mg to about 100 mg in extended release and c) entacapone or salts thereof from about 100 mg to about 1000 mg in immediate release form, optionally with other pharmaceutically acceptable excipients. The invention also relates to process of preparation of such compositions.

FIELD OF THE INVENTION

There is provided a single unit oral dose pharmaceutical compositioncomprising a) levodopa or salts thereof from about 50 mg to about 300 mgin extended release form, b) carbidopa or salts thereof from about 10 mgto about 100 mg in extended release and c) entacapone or salts thereoffrom about 100 mg to about 1000 mg in immediate release form, optionallywith other pharmaceutically acceptable excipients. The invention alsorelates to process of preparation of such compositions.

BACKGROUND OF THE INVENTION

Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), used inthe treatment of Parkinson's disease as an adjunct to levodopa/carbidopatherapy. The chemical name of entacapone is(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide.Its empirical formula is C₁₄H₁₅N₃O₅, and its structural formula is:

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is awhite, crystalline compound, slightly soluble in water. It is designatedchemically as (−)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxybenzene)propanoic acid. Its empirical formula is C₁₀H₁₄N₂O₄ and its structuralformula is:

Levodopa, an aromatic amino acid, is a white, crystalline compound,slightly soluble in water. It is designated chemically as(−)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empiricalformula is C₉H₁₁NO₄, and its structural formula is:

U.S. Pat. Nos. 6,500,867 and 6,797,732 disclose oral solid tabletcompositions comprising entacapone, levodopa and carbidopa, orpharmaceutically acceptable salts or hydrates thereof, and apharmaceutically acceptable excipient.

U.S. Pat. No. 7,094,427 and US 20040166159 disclose a compositioncomprising immediate release and extended release component.

US 20080051459 discloses a method of treating Parkinson's diseasecomprising administering pharmaceutically effective amount of acomposition comprising levodopa.

US 20070275060 disclose an extended release tablet comprising anextended release composition comprising levodopa; and an immediate orrapid release composition comprising carbidopa.

WO 07/073,702 discloses a multi-layered tablet providing three differentrelease profiles.

US 20060173074 disclose a method for the treatment of restless legssyndrome in a mammal.

Entacapone is available as immediate release composition under the tradename Comtan®. The marketed strength is 200 mg.

The triple combination of levodopa, carbidopa and entacapone isavailable as immediate release composition in different strengths. Forexample Stalevo® 50 (containing 12.5 mg of carbidopa, 50 mg of levodopaand 200 mg of entacapone), Stalevo® 75 (containing 18.75 mg ofcarbidopa, 75 mg of levodopa and 200 mg of entacapone), Stalevo® 100(containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg ofentacapone), Stalevo® 125 (31.2575 mg of carbidopa, 125 mg of levodopaand 200 mg of entacapone), Stalevo® 150 (containing 37.5 mg ofcarbidopa, 150 mg of levodopa and 200 mg of entacapone) and Stalevo® 200(containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg ofentacapone).

Parkinson's disease is a slowly progressive disease, in which thesymptoms get worse over time. Therefore, the symptoms will change andevolve. The pattern of symptoms can vary for each person. Over a numberof years, however, some people may see changes in the way theirmedication controls their symptoms. These changes are commonly known asmotor fluctuations. Over time, symptoms begin to come back before it istime to take next dose of levodopa medication. This change in symptomsis called “wearing-off.” As “wearing-off” becomes more noticeable, theamount of time for a good response to levodopa (known as “on” time)shortens and the time for poor response to levodopa (known as “off”time) may lengthen.

In the early stages of the disease, the brain is able to store enoughdopamine. This permits smoother release of dopamine in the brain. Italso provides a more constant control of symptoms. However, asParkinson's disease gets worse, the brain has fewer cells that can takeup levodopa and store it as dopamine for release when levels are low.Because of this reduced ability to store dopamine in the brain, symptomsmay return after shorter periods of time (e.g. “wearing-off”). Ifsomeone with a reduced ability to store dopamine is given too muchlevodopa, it may lead to side effects (e.g. dyskinesia).

It may be possible to better control these symptoms by changing oradjusting the treatment. As these motor fluctuations emerge, otherunwanted side effects may occur. These include involuntary movements,known as dyskinesia (e.g. twisting/turning movements) or dystonia (e.g.prolonged muscle cramping). The patients treated for Parkinson's diseasemay frequently develop motor fluctuations characterized by end-of-dosefailure, peak dose dyskinesia and akinesia, with levodopa therapy(“wearing off”) in which the patient suffers from unpredictable swingsfrom mobility to immobility. More than 50% of patients with Parkinson'sdisease develop motor response fluctuations (the “wearing off”phenomenon) after treatment with levodopa therapy. Symptoms of wearingoff include bradykinesia, dystonia, tremors, decreased manual dexterity,paresthesia, muscle pain, voice softness.

It is believed that the ‘wearing off’ effect can be minimized inpatients with a treatment regimen, which provides less rapid dissolutionproperties and providing a more even plasma level profile of levodopa.When administered in conjunction with levodopa, entacapone increases thebioavailability of levodopa by facilitating its passage across theblood-brain barrier. Hence, entacapone is approved as an adjunct tolevodopa therapy in Parkinson's disease. However, the dosage ofcurrently available formulation of carbidopa, levodopa and entacaponei.e. Stalevo® is given eight times a day. The frequent dosing of theseformulations is associated with more fluctuating plasma entacaponeconcentrations. Further, this regimen is not patient compliant.

Further, it has been observed that it is very inconvenient for thepatient to take a tablet of Sinemet CR and Comtan simultaneously numberof times a day, which leads to patient non-compliance especially inParkinson's patient. Further, literature also suggests when the threeingredients are present together vis a vis entacapone, carbidopa andlevodopa, it leads to decrease in bioavailability of entacapone andlevodopa. Therefore, the marketed formulation Stalevo containssubstantial portion of carbidopa separate from levodopa and carbidopa.Additionally, literature also reports destabilization of triplecombination formulation in presence of microcrystalline cellulose.

Hence, there is a need for patient compliant entacapone compositionand/or triple combination comprising levodopa, carbidopa and entacaponethat will dissolve slowly and provide a more even plasma level profilein patients with entacapone or levodopa/entacapone/carbidopa treatmentregimen.

SUMMARY OF THE INVENTION

In one aspect of the invention, there is provided a single unit oraldose pharmaceutical composition comprising a) levodopa or salts thereoffrom about 50 mg to about 300 mg in extended release form, b) carbidopaor salts thereof from about 10 mg to about 100 mg in extended releaseand c) entacapone or salts thereof from about 100 mg to about 1000 mg inimmediate release form, optionally with other pharmaceuticallyacceptable excipients.

In another aspect of the invention, there is provided a method oftreating Parkinson's disease in a mammal, comprising administering to amammal in need thereof, a single unit oral dose pharmaceuticalcomposition comprising a) levodopa or salts thereof from about 50 mg toabout 300 mg in extended release form, b) carbidopa or salts thereoffrom about 10 mg to about 100 mg in extended release and c) entacaponeor salts thereof from about 100 mg to about 1000 mg in immediate releaseform, optionally with other pharmaceutically acceptable excipients.

In another aspect of the invention, there is provided a method ofreducing the “wearing off” phenomena in Parkinson's patients, comprisingadministering to patient in need thereof, a single unit oral dosepharmaceutical composition comprising a) levodopa or salts thereof fromabout 50 mg to about 300 mg in extended release form, b) carbidopa orsalts thereof from about 10 mg to about 100 mg in extended release andc) entacapone or salts thereof from about 100 mg to about 1000 mg inimmediate release form, optionally with other pharmaceuticallyacceptable excipients.

In another aspect, there is provided a process for preparing a singleunit oral dose pharmaceutical composition comprising a) levodopa orsalts thereof from about 50 mg to about 300 mg in extended release form,b) carbidopa or salts thereof from about 10 mg to about 100 mg inextended release and c) entacapone or salts thereof from about 100 mg toabout 1000 mg in immediate release form, wherein the said processcomprises of: a) coating or mixing levodopa, carbidopa withpharmaceutically acceptable rate controlling polymers; b) entacaponewith one or more pharmaceutically acceptable excipients; c) mixing theblend of step a) and b) and converting it into suitable dosage form.

Embodiments of the pharmaceutical composition may include one or more ofthe following features. For example, the pharmaceutically acceptableexcipients may include one or more of fillers, binders, lubricants,sweeteners, coloring and flavoring agents, glidants, disintegrants, andthe like.

The details of one or more embodiments of the inventions are set forthin the description below. Other features, objects and advantages of theinventions will be apparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The inventors while working on the levodopa, entacapone, and carbidopacompositions have noticed that when levodopa or carbidopa is formulatedin extended release form, it allows for the continuous release oflevodopa or carbidopa over a prolonged period. Extended releasecomposition maintains extended release of levodopa and carbidopa therebyleading to non-fluctuating constant plasma levels of levodopa andcarbidopa. This further leads to reduction in the “wearing-off”phenomena, which is observed in Parkinson's patients due to fluctuatingplasma levels.

The inventors have further unexpectedly found that Sinemet CR and Comtancan be combined together in a single unit oral dose fixed combinationwithout effecting bioavailability of any one active in presence ofother. Even microcrystalline cellulose can also be used in the fixeddose combination without having any destabilizing effect on fixed dosecomposition. This fixed dose combination further leads to increase inpatient compliance.

The term ‘extended release’ as used herein refers to specific release ofdrug over a specified time period, which may extend from 4 hr to 24 hrsor more.

The extended release in the pharmaceutical composition may be achievedby one or more of coating or embedding in matrix using with hydrophilicor hydrophobic polymers or by attachment to ion-exchange resins.Further, extended release may be achieved by osmotic oral releasetechnology also.

One tablet of the said composition exhibits no significant difference inrate and/or extent of absorption of entacapone as compared to 2-4tablets of 200 mg of immediate release entacapone commercially marketedas Comtan® and levodopa and carbidopa as compared to one tablet ofSinemet® CR administered at the interval of 3-4 hours.

“Bioequivalency” is established by a 90% Confidence Interval (CI) ofbetween 0.80 and 1.25 for both C_(max) and AUC under USFDA regulatoryguidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI forC_(max) of between 0.70 to 1.43 under the European EMEA regulatoryguidelines.

The term “confidence interval” as used herein refers to plain meaningknown to ordinary skill in the art. Confidence interval refers to astatistical range with a specified probability that a given parameterlies within the range.

The term “covariance” as used herein refers to plain meaning known toordinary skill in the art. It is a statistical measure of the varianceof two random variables that are observed or measured in the same meantime period. This measure is equal to the product of the deviations ofcorresponding values of the two variables from their respective means.

The extended release pharmaceutical composition may include one or moreof tablet, bilayered tablet, trilayered tablet, tablet in tablet,capsule, powder, disc, caplet, granules, pellets, granules in capsule,minitablets, minitablets in capsule, pellets in capsule, sachet and thelike.

Levodopa, carbidopa or entacapone may be present in the form of powder,granules, pellets, beads, microtablets, minitablets and crystals.

The amount of entacapone in these pharmaceutical compositions variesfrom about 100 mg to about 1000 mg. The amount of levodopa in thesepharmaceutical compositions varies from about 50 mg to about 300 mg. Theamount of carbidopa in these pharmaceutical compositions varies fromabout 10 to about 100 mg.

Suitable rate controlling hydrophilic or hydrophobic polymers compriseone or more of polyvinyl acetate, cellulose acetate, cellulose acetatebutyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, afatty acid ester, an alkyl alcohol, a wax, shellac, rosin, zein(prolamine from corn), povidone, kollidon SR, a poly(meth)acrylate,microcrystalline cellulose or poly(ethylene oxide), polyuronic acidsalts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guargum, acacia, gellan gum locust bean gum, alkali metal salts of alginicacid or pectic acid, sodium alginate, potassium alginate, ammoniumalginate, hydroxypropyl cellulose, hydroxy ethyl cellulose,hydroxypropyl methyl cellulose, carboxyvinyl polymers, polymerizedgelatin, shellac, methacrylic acid copolymer type C NF, cellulosebutyrate phthalate, cellulose hydrogen phthalate, cellulose propionatephthalate, polyvinyl acetate phthalate (PVAP), cellulose acetatephthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate,dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose(CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), andacrylic acid polymers and copolymers like methyl acrylate, ethylacrylate, methyl methacrylate and/or ethyl methacrylate with copolymersof acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL,Eudragit RS) and the like. Polymer may be used from 0.1-50% by weight ofthe composition.

The extended release pharmaceutical composition may comprise one or morepharmaceutically acceptable excipients. The pharmaceutically acceptableexcipients may include diluents, binders, disintegrants, surfactants,lubricants, glidants and the like.

Suitable binder may one or more of, povidone, starch, stearic acid,gums, hydroxypropylmethyl cellulose and the like. Binder may be usedfrom 0.1% to 40% by weight of the composition

Suitable diluent may be one or more of, microcrystalline cellulose,mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch,powdered sugar and the like. Diluent may be used from 1 to 50% by weightof the composition.

Suitable disintegrant may be one or more of starch, croscarmellosesodium, crospovidone, sodium starch glycolate and the like. Disintegrantmay be used from 2-20% by weight of the composition.

Suitable lubricant may be one or more of magnesium stearate, zincstearate, calcium stearate, stearic acid, sodium stearyl fumarate,hydrogenated vegetable oil, glyceryl behenate and the like. Lubricantmay be used from 0.1-5% by weight of the composition.

Suitable glidant may be one or more of colloidal silicon dioxide, talcor cornstarch and the like. Glidant may be used from 0.1-5% by weight ofthe composition.

The pharmaceutical composition may be prepared by mixing entacapone withpharmaceutically acceptable excipients to form an entacapone blend.Levodopa and carbidopa may be mixed with one or more pharmaceuticallyacceptable polymers and excipients to form levodopa carbidopa blend. Theentacapone blend and levodopa-carbidopa blend may be mixed with otherpharmaceutically acceptable excipients and converted into suitabledosage form.

The invention is further illustrated by the following examples which areprovided merely to be exemplary of the invention and do not limit thescope of the invention. Certain modifications and equivalents will beapparent to those skilled in the art and are intended to be includedwithin the scope of the invention.

EXAMPLES

The composition of batches is provided in Table 1 to 23. Followingformulations are representatives of the preferred compositions of theinvention. The preparation of example is detailed below.

Example-I

TABLE 1 Pharmaceutical composition of the invention Ingredients % w/wEntacapone IR layer/Portion Entacapone 38.41 Mannitol 6.73 Sodium starchglycolate 3.85 Corn Starch 9.42 Croscarmellose sodium 4.62 Povidone 1.51Purified water q.s. Extragranular Ingredients Magnesium stearate 0.77Levodopa and Carbidopa CR layer/Portion Levodopa 19.22 Carbidopa 5.19Microcrystalline Cellulose 4.62 Povidone 3.46 Purified Water q.s.Extragranular Ingredients Poly Vinyl Pyrrolidone 1.73 Magnesium Stearate0.38

Procedure: Entacapone Layer/Portion:

Entacapone and mannitol were co-milled and sifted. Cornstarch,croscarmellose sodium and sodium starch glycolate were co-siftedseparately. The materials were placed in granulator and mixed. Povidonewas dissolved in purified water and granulated with the mixed material.The granulated contents were dried. Magnesium stearate was sifted andmixed with the dried granules.

Levodopa and Carbidopa Layer/Portion:

Levodopa, Carbidopa and microcrystalline cellulose were co-sifted andmixed. Povidone was dissolved in Purified water and granulate with abovemixed contents. The granulated contents were dried. Magnesium stearatewas sifted with polyvinyl pyrrolidone and mixed with the dried granules.

Compression

Both the entacapone layer/portion and Levodopa and Carbidopalayer/portion were compressed into bilayered tablets or into tablet intablet with entacapone surrounding the levodopa-carbidopa inlay tablet.

TABLE 2 Dissolution data of composition prepared as per example I. %Drug released Time (hrs) Levodopa Carbidopa 0.5 45 45 1 58 58 2.5 94 924 96 95 Time (min) % Drug released (Entacapone) 10 51 20 70 30 79 45 85

Table 2 provides the dissolution data of composition prepared as performula given in table 1. For determination of drug release rate ofentacapone, USP Type 2 Apparatus (rpm 50) was used wherein 900 ml of pH5.5 phosphate buffer at 37° C.±0.5° C. was used as medium. Further, fordetermination of drug release rate of levodopa and carbidopa, USP Type 2Apparatus (rpm 50) was used wherein 900 ml of 0.1 N HCl at 37° C.±0.5°C. was used as medium.

Example-II

TABLE 3 Pharmaceutical composition of the invention Ingredients % w/wEntacapone layer/Portion Entacapone 28.57 Mannitol 5.00 Sodium starchglycolate 2.86 Corn Starch 7.00 Croscarmellose sodium 3.43 Povidone 1.14Purified water q.s. Extragranular Ingredients Magnesium stearate 0.57Levodopa and Carbidopa CR layer/Portion Levodopa 28.57 Carbidopa 7.71Microcrystalline Cellulose 6.86 Povidone 5.14 Purified Water q.s.Extragranular Ingredients PVP 2.57 Magnesium Stearate 0.57

Procedure: Entacapone Layer/Portion:

Entacapone and mannitol were co-milled and sifted. Corn starch,croscarmellose sodium and sodium starch glycolate were co-siftedseparately. The materials were placed in granulator and mixed. Povidonewas dissolved in purified water and granulated with the mixed material.The granulated contents were dried. Magnesium stearate was sifted andmixed with the dried granules.

Levodopa and Carbidopa Layer/Portion:

Levodopa, Carbidopa and microcrystalline cellulose were co-sifted andmixed. Povidone was dissolved in Purified water and granulate with abovemixed contents. The granulated contents were dried. Magnesium stearatewas sifted with Poly Vinyl Pyrrolidone and mixed with the driedgranules.

Compression

Both the entacapone layer/portion and Levodopa and Carbidopalayer/portion were compressed into bilayered tablets or into tablet intablet with entacapone surrounding the levodopa-carbidopa inlay tablet.

TABLE 4 Dissolution data of composition prepared as per example II. %Drug released Time (hrs) Levodopa Carbidopa 0.5 43 43 1 58 58 2.5 88 894 98 98 Time (min) % Drug released (Entacapone) 10 59 20 76 30 82 45 87

Table 4 provides the dissolution data of composition prepared as performula given in table 3. For determination of drug release rate ofentacapone, USP Type 2 Apparatus (rpm 50) was used wherein 900 ml of pH5.5 phosphate buffer at 37° C.±0.5° C. was used as medium. Further, fordetermination of drug release rate of levodopa and carbidopa, USP Type 2Apparatus (rpm 50) was used wherein 900 ml of 0.1 N HCl at 37° C.±0.5°C. was used as medium.

Example-III

TABLE 5 Pharmaceutical composition of the invention Ingredients % w/wEntacapone IR layer/Portion Entacapone 36.36 Mannitol 21.27 Povidone3.27 Crospovidone 4.36 Magnesium stearate 0.54 Extragranular IngredientsTalc 0.90 Magnesium stearate 0.54 Levodopa and Carbidopa CRlayer/Portion Levodopa 18.18 Carbidopa 4.90 Microcrystalline Cellulose4.36 Povidone 3.27 Purified Water q.s. Extragranular Ingredients PVP0.16 Magnesium Stearate 0.03

Procedure: Entacapone Layer/portion:

Entacapone and mannitol were co-milled and sifted. Povidone,crospovidone and mannitol were co-sifted separately. The materials weremixed to form a bulk. Magnesium stearate was sifted and mixed with theabove bulk. This was compacted and crushed. Magnesium stearate and talcwere sifted separately and was mixed with the crushed material.

Levodopa and Carbidopa Layer/Portion:

Levodopa, Carbidopa and microcrystalline cellulose were co-sifted andmixed. Povidone was dissolved in Purified water and granulate with abovemixed contents. The granulated contents were dried. Magnesium stearatewas sifted with Poly Vinyl Pyrrolidone and mixed with the driedgranules.

Compression

Both the entacapone layer/portion and Levodopa and Carbidopalayer/portion were compressed into bilayered tablets or into tablet intablet with entacapone surrounding the levodopa-carbidopa inlay tablet.

Example-IV

TABLE 6 Pharmaceutical composition of the invention Ingredients % w/wEntacapone IR layer/Portion Entacapone 27.39 Mannitol 21.27 Povidone2.47 Crospovidone 3.29 Magnesium stearate 0.41 Extragranular IngredientsTalc 0.68 Magnesium stearate 0.41 Levodopa and Carbidopa CRlayer/Portion Levodopa 27.39 Carbidopa 7.39 Microcrystalline Cellulose6.58 Povidone 4.93 Purified Water q.s. Extragranular Ingredients PVP2.46 Magnesium Stearate 0.54

Procedure: Entacapone Layer/Portion:

Entacapone and mannitol were co-milled and sifted. Povidone,crospovidone and mannitol were co-sifted separately. The materials weremixed to form a bulk. Magnesium stearate was sifted and mixed with theabove bulk. This was compacted and crushed. Magnesium stearate and talcwere sifted separately and was mixed with the crushed material.

Levodopa and Carbidopa Layer/Portion:

Levodopa, Carbidopa and microcrystalline cellulose were co-sifted andmixed. Povidone was dissolved in Purified water and granulate with abovemixed contents. The granulated contents were dried. Magnesium stearatewas sifted with Poly Vinyl Pyrrolidone and mixed with the driedgranules.

Compression

Both the entacapone layer/portion and Levodopa and Carbidopalayer/portion were compressed into bilayered tablets or into tablet intablet with entacapone surrounding the levodopa-carbidopa inlay tablet.

Example-V

TABLE 7 Pharmaceutical composition of the invention Ingredient % w/wInner LC-ER core tablet Levodopa 30.77 Carbidopa 8.31 Hydroxy Propylcellulose 4.62 Mannitol 1.54 Povidone K90 0.46 Isopropyl alcohol 0.00Dichloromethane 0.00 Magnesium stearate 0.46 Inner ER core tablet WeightExternal Entacapone IR granules Entacapone 30.77 Mannitol 25 5.38 Sodiumstarch glycolate 3.08 Croscarmellose sodium 3.69 Corn starch 7.54Povidone K30 1.23 water 0.00 Sodium starch glycolate 1.54 Magnesiumstearate 0.62 External Entacpone IR granules Weight Total Tablet weight

Procedure—Inner LC-ER Core Tablet

Levodopa, Carbidopa, Hydroxy Propyl cellulose & mannitol were co-siftedand mixed. Povidone K90 was dissolved in Isopropyl alcohol &Dichloromethane. The bulk of step 1 was granulated using step 2 solutionand granules were dried. Magnesium stearate was added to preparedgranules and lubricated granules were compressed to obtain core tablets.

External Entacapone IR Granules

Entacapone & mannitol were co-milled. Sodium starch glycolate,Croscarmellose sodium, Corn starch were co-sifted. Povidone K30 wasdissolved in purified water and used to granulate the bulk of step 1.Granules were dried. Sodium starch glycolate was sifted through suitablemesh and added to above granules. Magnesium stearate was added to abovemix.

Compression

Tablet in tablet of inner LC ER core tablets & external Entacpone IRgranules were compressed using suitable compression machine

TABLE 8 LEVODOPA CARBIDOPA Time Sinemet CR Example-1 Sinemet CRExample-1 0 0 0 0 0 15 20 15 23 16 30 37 40 38 40 45 52 57 52 58 60 6670 65 70 75 77 79 75 79 90 85 86 81 86 120 95 96 90 95 150 100 102 94101 180 102 103 97 103 For Entacapone Time Comtan Example-V 0 0 0 5 1717 10 47 39 20 88 72 30 98 82 45 101 90

Table 8 provides the dissolution data of composition prepared as performula given in table 7. For determination of drug release rate ofentacapone, USP Type 2 Apparatus (rpm 50) was used wherein 900 ml of pH5.5 phosphate buffer at 37° C.±0.5° C. was used as medium. Further, fordetermination of drug release rate of levodopa and carbidopa, USP Type 2Apparatus (rpm 50) was used wherein 900 ml of 0.1 N HCl at 37° C.±0.5°C. was used as medium.

TABLE 9 Bio Data (Fasted State) PK Ratio % 90% CI Parameters (T/R) LowerLimit Upper Limit Intra-CV (%) For Entacapone - Cmax 105.42 75.03 148.1156.28 AUC t 106.92 91.78 124.56 23.89 AUV inf 106.14 91.39 123.27 23.89For Carbidopa - Cmax 142.51 120.86 168.05 25.84 AUC t 142.04 120.91166.86 25.23 AUV inf 141.54 120.78 165.87 24.84 For Levodopa - Cmax125.57 109.25 144.32 21.73 AUC t 112.57 97.92 129.41 21.76 AUV inf112.58 97.88 129.49 21.84

Table 9 provides bio profile of LC ER and Entacapone IR combinationtablets prepared as per example V under fasting condition versusReference product Comtan® 200 mg+one tablet of Sinemet CR (Manufacturer:Merck; Levodopa 200+Carbidopa 50 mg ER tablet. Study design includefasting two-way cross-over bioequivalence study in 15 normal, adult,human subjects under fed condition

Example-VI

TABLE 10 Pharmaceutical composition of the invention Ingredient % w/wInner LC ER core tablet Levodopa 30.30 Carbidopa 8.18 Hydroxy Propylcellulose 4.55 Mannitol 1.97 Methacrylic acid copolymer 1.52 Isopropylalcohol — Dichloromethane — Magnesium stearate 0.45 External EntacponeIR granules Entacapone 30.30 Mannitol 25 5.30 Sodium starch glycolate3.03 Croscarmellose sodium 3.64 Corn starch 7.42 Povidone K30 1.21 water— Sodium starch glycolate 1.52 Magnesium stearate 0.61 Total Tabletweight

Procedure: Inner LC-ER Core Tablet

Levodopa, Carbidopa, Hydroxy Propyl cellulose & mannitol were co-siftedand mixed. Methacrylic acid copolymer was dissolved in Isopropyl alcohol& Dichloromethane. The bulk of step 1 was granulated using step 2solution and granules were dried. Magnesium stearate was added to thebulk of step 3 and mixed. The bulk of step 4 was granulated usingsuitable punches to obtain core tablets.

External Entacapone IR Granules

Entacapone & mannitol were mixed and milled. Sodium starch glycolate,Croscarmellose sodium, Corn starch were co-sifted and mixed. PovidoneK30 in was dissolved in purified water. The bulk of step 7 wasgranulated using step 8 solution and granules were dried. Sodium starchglycolate was added to the bulk of step 9 and mixed. Magnesium stearatewas added to the bulk of step 10 and mixed.

Compression

Tablet in tablet dosage form was prepared using inner LC ER core tablets& external Entacpone IR granules using suitable compression machine.

1. A single unit oral dose pharmaceutical composition comprising a)levodopa or salts thereof from about 50 mg to about 300 mg in extendedrelease form, b) carbidopa or salts thereof from about 10 mg to about100 mg in extended release and c) entacapone or salts thereof from about100 mg to about 1000 mg in immediate release form, optionally with otherpharmaceutically acceptable excipients.
 2. A method of treatingParkinson's disease in a mammal, comprising administering to a mammal inneed thereof, a single unit oral dose pharmaceutical compositioncomprising a) levodopa or salts thereof from about 50 mg to about 300 mgin extended release form, b) carbidopa or salts thereof from about 10 mgto about 100 mg in extended release and c) entacapone or salts thereoffrom about 100 mg to about 1000 mg in immediate release form, optionallywith other pharmaceutically acceptable excipients.
 3. A method ofreducing the “wearing off” phenomena in Parkinson's patients, comprisingadministering to patient in need thereof, a single unit oral dosepharmaceutical composition comprising a) levodopa or salts thereof fromabout 50 mg to about 300 mg in extended release form, b) carbidopa orsalts thereof from about 10 mg to about 100 mg in extended release andc) entacapone or salts thereof from about 100 mg to about 1000 mg inimmediate release form, optionally with other pharmaceuticallyacceptable excipients.
 4. A process for preparing a single unit oraldose pharmaceutical composition comprising a) levodopa or salts thereoffrom about 50 mg to about 300 mg in extended release form, b) carbidopaor salts thereof from about 10 mg to about 100 mg in extended releaseand c) entacapone or salts thereof from about 100 mg to about 1000 mg inimmediate release form, wherein said process comprises of: a) coating ormixing levodopa, carbidopa with pharmaceutically acceptable ratecontrolling polymers; b) entacapone with one or more pharmaceuticallyacceptable excipients; c) mixing the blend of step a) and b) andconverting it into suitable dosage form. 5) The composition as claimedin 1, wherein the composition comprises one or more of tablet, bilayeredtablet, trilayered tablet, capsule, powder, disc, caplet, granules,pellets, granules in capsule, minitablets, minitablets in capsule,pellets in capsule and sachet. 6) The composition as claimed in 1,wherein the extended release is achieved by coating or mixing levodopaand carbidopa with one or more pharmaceutically acceptable ratecontrolling polymers. 7) The composition as claimed in 6, wherein thepharmaceutically acceptable rate controlling polymers comprise one ormore of polyvinyl acetate, cellulose acetate, cellulose acetatebutyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, afatty acid ester, an alkyl alcohol, a wax, shellac, rosin, zein(prolamine from corn), povidone, kollidon SR, a poly(meth)acrylate,microcrystalline cellulose or poly(ethylene oxide), polyuronic acidsalts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guargum, acacia, gellan gum locust bean gum, alkali metal salts of alginicacid or pectic acid, sodium alginate, potassium alginate, ammoniumalginate, hydroxypropyl cellulose, hydroxy ethyl cellulose,hydroxypropyl methyl cellulose, carboxyvinyl polymers, polymerizedgelatin, shellac, methacrylic acid copolymer type C NF, cellulosebutyrate phthalate, cellulose hydrogen phthalate, cellulose propionatephthalate, polyvinyl acetate phthalate (PVAP), cellulose acetatephthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate,dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose(CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), andacrylic acid polymers and copolymers like methyl acrylate, ethylacrylate, methyl methacrylate and/or ethyl methacrylate with copolymersof acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL,Eudragit RS). 8) The pharmaceutical composition of claim 1, wherein onetablet of the said composition exhibits no significant difference inrate and/or extent of absorption of entacapone as compared to 2-4tablets of 200 mg of immediate release entacapone commercially marketedas Comtan® and no significant difference in rate and/or extent ofabsorption of levodopa and carbidopa as compared to one tablet ofSinemet® CR administered at the interval of 3-4 hours. 9) The method oftreatment of claim 2, wherein one tablet of the said compositionexhibits no significant difference in rate and/or extent of absorptionof entacapone as compared to 2-4 tablets of 200 mg of immediate releaseentacapone commercially marketed as Comtan® and no significantdifference in rate and/or extent of absorption of levodopa and carbidopaas compared to one tablet of Sinemet® CR administered at the interval of3-4 hours. 10) The method of reducing the “wearing off” phenomena ofclaim 3, wherein one tablet of the said composition exhibits nosignificant difference in rate and/or extent of absorption of entacaponeas compared to 2-4 tablets of 200 mg of immediate release entacaponecommercially marketed as Comtan® and no significant difference in rateand/or extent of absorption of levodopa and carbidopa as compared to onetablet of Sinemet® CR administered at the interval of 3-4 hours.